While manganese (Mn) is an essential trace metal, excess exposure due to occupational settings can cause damage to the nervous system. Symptoms of Mn intoxication ("manganism") resemble those in idiopathic Parkinson's disease and usually become progressive and irreversible, making early diagnosis crucial for prevention of Mn intoxication in the occupational and environmental setting. Studies on rodents have linked increased Mn concentrations with alterations in the content of neurotransmitters in the basal ganglia brain region, however the dose-dependency of such alterations is controversial. Using novel, non-invasive approaches to detect concentration changes of the neurotransmitters 3-aminobutyric acid (GABA) and glutamate (Glu) in the human brain and studying their correlation to other Mn exposure indices, such as blood, urine and air samples, may lead to new insights about the mechanism on Mn-induced toxicity and potentially result in a non-invasive biomarker, which may be used for early, pre-symptomatic clinical diagnosis of Mn intoxication. Therefore the primary objective of the proposed work is to use a combined magnetic resonance imaging (MRI) and spectroscopy (MRS) technique to detect and quantify changes of GABA and Glu in several relevant brain regions of Mn-exposed subjects and to study their dose- dependency. The following two hypotheses will be tested: (1) Mn exposure leads to increased GABA levels in the thalamic brain region, to decreased Glu levels in cortical brain regions and to increased Glu levels in the pallidal brain region, and (2) such changes, together with the known MRI signal intensity increase in the globus pallidus due to Mn deposition in this brain region, correlate with the extent of Mn exposure, as measured by other external and internal exposure indices. The study cohort will consist of 30 Mn-exposed and 20 control subjects. The exposed group will be subdivided into 10 Mn-exposed patients with manganism symptoms, 10 workers from a Fe-Mn-alloy manufacture in China performing jobs with known high Mn exposure, but without clinical symptoms, and 10 workers from low Mn-exposure areas in the same factory. This subdivision allows for the testing of the dose dependency of the sought changes in brain metabolism. Recently developed MRS techniques, allowing for the non-invasive detection and quantification of GABA and Glu in the human brain will be used to measure concentrations of these neurotransmitters and other brain metabolites in several different brain areas. To assess other external and internal Mn exposure indices (1) air samples will be taken at the current or former working places of the subjects, (2) urine and blood samples will be collected and (3) each subject will undergo physiological examination and neurobehavioral testing. The knowledge to be gained from this work may for the first time in human studies allow for conclusions on the vulnerability of glutamatergic and GABAergic brain systems to Mn and thus help advance novel therapeutic strategies. PUBLIC HEALTH RELEVANCE: Excessive occupational exposure to manganese in the alloying and steel industry is known to cause Parkinson-like symptoms, which progress even after the cessation of the exposure. Neither a biomarker for early, pre-symptomatic diagnosis, nor effective treatment options exist to date. Using novel, non-invasive techniques such as magnetic resonance imaging and magnetic resonance spectroscopy to measure the changes in brain metabolism caused by manganese exposure, and studying the dose-dependence of such changes, will provide critical insight to the mechanism of manganese-induced neurotoxicity and will benefit early clinical diagnosis.